In:
Journal of Virology, American Society for Microbiology, Vol. 86, No. 24 ( 2012-12-15), p. 13423-13433
Abstract:
Certain immune-driven mutations in HIV-1, such as those arising in p24 Gag , decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24 Gag M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) ( P = 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles ( P 〈 0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24 Gag codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.
Type of Medium:
Online Resource
ISSN:
0022-538X
,
1098-5514
DOI:
10.1128/JVI.02171-12
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2012
detail.hit.zdb_id:
1495529-5
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